Verapamil is presently in clinical use as the racemate and is used extensively for treatment of hypertension. The (S)-isomer has the majority of the calcium channel antagonist activity, see DE-A-2059923, whilst the (R)-isomer differs in having sodium channel and other cell-pump actions in addition to a higher bioavailability, with slower clearance rate. For the treatment of hypertension, the (S)-isomer may provide a safer treatment than the racemate, with an extended therapeutic window. The (R)-isomer may be of benefit for the treatment of multidrug resistance in cancer chemotherapy, see J.F. Eliason, H. Ramuz and F. Kaufmann, Int. J. Cancer (1990) 46: 113-117; in this case hypotensive action by admixture with (S)-isomer would be undesirable. The preferential use of one of the isomers for migraine treatment is also possible, see S.J. Peroutka, Ann. Neurol. (1988) 23: 500-504.
The preparation of the single enantiomers of verapamil is a difficult chemical problem. DE-A-3723654 discloses that the isomers have been separated by resolution with, for example, binaphthol bis (dihydrogen phosphate), but this would appear to be an expensive process. Similarly, the resolution of a racemic carboxylic acid precursor with brucine, as disclosed in DE-A-2059923, and the multi-step process thereafter, does not look attractive for bulk manufacture, nor does a lengthy synthesis from the enantiomers of propane-1,2-diol, see L.J. Theodore and W.L. Nelson, J. Org. Chem. (1987) 52: 1309-1315, or separation of the final product by chromatography, see JP-A-03027326.